| Homer was originally cloned as a neuronal immediate early gene (IEG), and the Homer protein targets to excitatory synapses. Three Homer genes have been cloned (Homer 1, Homer 2, Homer 3) since the discovery of the IEG, Homer 1a, but unlike Homer 1a, these three Homer genes have a C-terminal coiled-coil domain. All Homer forms have an N-terminal EVH (E&barbelow;na-V&barbelow;ASP H&barbelow;omology) domain. Yeast two-hybrid analysis using Homer EVH as bait identified mGluR1α/5, Shank, human INADL (hINADL), and NMDAR 2D (NR2D) as interactors. Homer family members bind to proline-rich sequences in group 1 metabotropic glutamate receptors (mGluRs), NR2D, IP3 receptors (IP3Rs), and the Shank family of scaffolding proteins. The consensus binding site for Homer is PXXF (PXXY for NR2D). Homer is believed to function as an adapter protein that assists in the assembly of proteins involved in signaling and synaptogenesis.; Here, I report the assembly of a physically coupled complex of TRPC1-Homer-IP3R. TRPC1 belongs to the transient receptor potential (TRP) family of ion channels and functions as calcium influx channel that can be activated by store depletion or agonists. Depletion of store Ca2+ dissociates the TRPC1-Homer complex, while store overloading enhances its formation. Homer binds TRPC1 via the N- (LPSSP) and C-terminal (LPPPF) tails, and interruption of this interaction by mutations of TRPC1 results in spontaneously active channels that cannot be further activated by store-depletion or agonists. The immediate early gene form of Homer (H1a), which cannot cross-link, also produces a spontaneously active channel and defines a natural regulatory mechanism for TRPC activity that targets conformational assembly of the channel. |
